Effective detection and diagnosis of certain disorders such as cancer have long been an object of intense research. The development of targeted pharmaceuticals and monoclonal antibodies has significantly improved the ability to target and deliver diagnostic agents to specific target cells, tissues or organs. Of particular interest in the diagnosis of many forms of carcinoma is the use of antibodies, both polyclonal and monoclonal, to specifically bind to tissues or molecules. The use of such antibodies continues to be an important tool in cancer detection through imaging. To be useful for such imaging purposes, pharamaceuticals and antibodies must first be labeled with an appropriate radionuclide.
Efficient labeling of antibodies, especially monoclonal antibodies, depends on a number of factors, including the characteristics of the radionuclide itself and the method and manner of its incorporation into the protein. The chemical changes inherent in the labeling procedures often cause significant effects on the functional integrity of antibodies and their fragments. To date, most labeling studies for radioimmunoimaging have been carried out with iodine or indium radionuclides. Radiometal labeling of antibodies via the bifunctional chelate approach helps avoid the deleterious effects of oxidation experienced in common iodination reactions. Labeling with metals also overcomes the problems of in vivo deiodination by tumor and normal tissues, particularly when using rapidly internalized antibodies.
The experience with I-131 as the antibody radiolabel has shown that it has several disadvantages, the most significant being high gamma energy, in vivo deiodination, high radiation background, the need for late imaging and the need to use a relatively high radiation dose. Use of In-111 rather than I-131 as the radiolabel for imaging overcomes some of the problems with I-131 because of its good tumor uptake and good imaging photons; however, In-111 presents disadvantages that limit the value of its use. These include the chemistry difficulties presented by this radionuclide, the slow blood clearance of In-111, the high liver and whole body retention of the nuclide, which increases radiation dose and makes it difficult to localize liver metastases, the need to do late imaging, and the fact that SPECT imaging is suboptimal due to decreased photon availability at 3-6 days after injection.
The present invention covers the use of the radionuclide lead-203 as an alternative to I-131 or In-111 for pharmaceutical and antibody labeling for radioimaging in order to overcome the disadvantages associated with I-131 and In-111. Pb-203 possesses good imaging photons and, when used as an antibody label, exhibits good tumor uptake, higher residence time in tumor, good tumor to background ratios, early imaging and SPECT imaging feasibility, the ability to localize liver metastases and faster blood and whole body clearance.
In the present invention, antibodies or active antibody fragments are covalently combined with the radionuclide lead-203. These Pb-203/antibody conjugates retain the antibody specificity and activity, and are useful in diagnostic techniques. The Pb-203/antibody conjugates of the present invention exhibit improved biodistribution and other characteristics in comparison to the most widely used radionuclides, indium-111 and iodine-131.
The superiority of the present invention over known compositions rests in the discovery that Pb-203, which has favorable nuclear and chemical properties, displays superior in vivo behavior when used as a label for pharmaceuticals, antibodies and antibody fragments. In this regard, Pb-203 serves as an alternate and better radiolabel for immunoscintigraphy due to its high tumor uptake and relatively rapid clearance from the blood, liver, and whole body, in contrast to the high blood and liver retention associated with the use of indium-111. The production routes to Pb-203 include: ##STR1## Pb-203 decays by electron capture (emitting no betas) with a primary emission of 279 KeV (77%), suitable for imaging. The chemistry of lead (II) is favorable for attachment through chelation techniques to a variety of ligands with diverse functional groups and structures.
It is an object of the present invention to provide a composition comprising Pb-203 bonded to a pharmaceutical or covalently bonded to an antibody or antibody fragment. The covalent bond involves the use of a bifunctional chelating agent.
The 2.17 day half-life of the Pb-203 conjugate herein described is also compatible with another object of the present invention, limiting extended doses of radiation to the patient, particularly in situations in which delayed imaging or emission is either necessary or desirable.
It is also an object of the present invention to provide a Pb-203 conjugate in which many radionuclides may be coupled to an antibody or antibody fragment.
Although tumor imaging and diagnosis is one application of the Pb-203/antibody conjugates, antibodies to a variety of other antigens broaden their usefulness. For example, antibodies to blood cells, fibrin, viruses, and specific tissues, can be conjugated to Pb-203 and used to image and detect clots, abscesses, inflammations, phlebitis, embolisms, and other viral infections and organ abnormalities.